(Applicant's Abstract) In Project 5 we propose to define the role of the fibroblastic foci and myofibroblast presence in IPF/UIP pathogenesis, to test an antiproliferative therapy for this disorder, and develop surrogate markers which predict outcome. Because of its antiproliferative properties and antagonism of transforming growth factor-beta-1 (TGF-b1) functions in vitro, as well as TGFb-1 driven myofibroblast generation, we propose to study the efficacy of interferon gamma (IFN) (subcutaneous and inhaled) in idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). In the recently initiated phase III trial, we will define surrogate markers of outcome; to include dyspnea scores, physiologic tests, quantitative image analysis of the high resolution computed tomographic images, and fibroproliferative biomarkers. Recently, we were instrumental in organizing an NHLBI workshop which proposed systematic evaluation of several available novel therapeutic agents that could abrogate the fibroproliferative response. Myofibroblast apoptosis, proliferation, clonality and structure of fibroblastic foci will be compared to bronchiolitis obliterans organizing pneumonia (BOOP), a disease whose positive outcome exceeds IPF/UIP. Gene expression patterns of whole IPF[UIP lung will be analyzed by microarray and compared to normals and BOOP to determine differences and characteristic patterns. Microdissection of fibroblastic foci in IPF1UIP and Masson's bodies of BOOP will be performed. Based on this and utilizing laser capture microdissection BOOP will be performed to determine diagnostic patterns. The goal is to determine gene expression patterns of IPF/UIP and BOOP, which predict clinical behavior and are typical for that particular disease. We will also determine within the IPFIUIP group which genes reflect a bad vs. improved prognosis and the differential gene expression pattern between Fibroblastic foci (IPF/IJIP) and Masson's bodies.